Biology subjects

Aronoff, J. E.

Publications and source records attributed to Aronoff, J. E..

2 recordsLinked to original sources

bioRxiv2026

Inflammaging mediates testosterone declines in men while maintaining high testosterone increases mortality risk

Later life is accompanied by testosterone declines alongside the development of chronic inflammation, termed inflammaging. A new theoretical model posits these processes are related through an energetic trade-off. As somatic damage accumulates, this should chronically activate the energetically costly inflammatory response. As an energy conserving response to promote cellular repair, testosterone production is expected to be suppressed. Consistent with this model, we find that markers of inflammaging, including IL-6 and GDF-15, mediate age-related testosterone declines in a large sample of male participants from the UK Biobank (n = 18,347, mean age 57 years, range 40-70). GDF-15, a marker of chronic inflammation and a key metabolic stress signaling protein, was the strongest predictor and mediator of testosterone declines. Further, individuals with high testosterone given their health and level of inflammation showed elevated mortality risk over follow up, consistent with a trade-off between maintenance and reproduction. Our results highlight the importance of considering energetic trade-offs to understand later life testosterone declines. They also highlight the importance of alleviating cellular damage that augments inflammaging and its down-stream hormonal effects. Finally, our study raises concern for exogenous testosterone therapies in the context of chronic inflammation, which could increase mortality risk. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=103 SRC="FIGDIR/small/730222v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@19b673eorg.highwire.dtl.DTLVardef@19734feorg.highwire.dtl.DTLVardef@18149dorg.highwire.dtl.DTLVardef@f162f4_HPS_FORMAT_FIGEXP M_FIG C_FIG

evolutionary biology↗

bioRxiv2025

Evidence for an energetic trade-off model linking inflammaging and immunosenescence in the US Health and Retirement Study and UK Biobank

Later life is characterized by the development of chronic inflammation, termed inflammaging, alongside changes in immune cell profiles, or immunosenescence. While these features contribute to health risk, they have also been interpreted as adaptive remodeling of the immune system in response to accumulating somatic damage. Here we consider a recently developed theoretical framework to understand these processes as interrelated: the Brain-Body Energy Conservation model of aging. This model views functional declines, such as immunosenescence, as part of an energy conserving response to the rising energy expenditure of inflammaging. This response promotes short term survival against somatic damage at the expense of future health risk. For example, naive T cells, which enhance defense against future infections, decline with age. We find evidence consistent with this model in the US Health and Retirement Study (HRS) and UK Biobank (UKB). TNFR1, a key marker of inflammaging, mediated 10% and 5% of the age-related declines in naive CD4T and CD8T cells respectively in the HRS (n = 8,261). Consistent with an impaired immune response to future infections, TNFR1 also mediated 16% of the age-related increased risk of hospitalization or death from COVID-19 in the UKB (n = 522 hospitalized or died, full sample n = 40,638). GDF15, which is produced in response to metabolic stress and has been found to induce immune tolerance in response to chronic inflammation, mediated 28% of the TNFR1-related COVID-19 health risk, as well as 38% of the age-related increased risk independent of TNFR1.

evolutionary biology↗